June, 1937
PREPARATION OF PRIMARY SATURATED ALKYLPHENOLS
’The one tertiary isomer is more soluble than any of the three secondary isomers which in turn are more soluble than any of the four primary isomers. The solubility increases as the hydroxyl group approaches the center of the molecule. Limitation of the comparisons t o either the pri-
1113
mary or the secondary group reveals that the more compact the molecular structure, the greater is the aqueous solubility. The solubility of all eight isomers decreases as the temperature increases from 20 to 30’. GREENSBORO, N. C.
RECEIVED APRIL5, 1937
[CONTRIBUTION FROM THE CHEMICAL LABORATORIES OF THE WASHINGTO~ SQUARE COLLEGE OF NEWYORK UNIVERSITY AND ST.JOHN’S UNIVERSIN]
Equimolar Condensations of Aldehydes with Phenols. The Preparation of Primary Saturated Alkylphenols’ BY JOSEPHB. NIEDERL, VICTOR NIEDERL, S. SHAPIRO~ AND MARTIN E. MCGREAL Condensation of carbonyl compounds (alde- takes place as in aldol condensations; (c) to inveshydes and ketones) with multimolar quantities of tigate the chemical nature of the intermediate a phenol usually results in the formation of the polymer; and (d) t o investigate the behavior of corresponding alkylidene-di-phenol. a Dianin and these aldehyde-phenol polymers upon pyrolysis, von Braun,’ however, made the observation that particularly as t o the possibility whether a similar saturated secondary or tertiary alkylphenols are “disproportionation” could be observed in the obtained when the intermediate polymeric conden- aldehyde series as has already been established in sation products resulting from the action of hydro- isolated cases in the ketone and indane ~ e r i e s . ~ chloric acid upon a mixture consisting of several Although the end-products, the saturated primary moles of a phenol and one mole of a ketone, ali- alkylphenols, could be identified easily, analysis of phatic (di-n-propyl, methyl hexyl ketone and di- the intermediate polymeric condensation products chloroacetone) as well as aromatic ketones (nce- did not lead t o uniformly interpretable results. tophenone, w-chloroacetophenone) are subjected Some of these products, when reprecipitated, powto pyrolysis. The formation of saturated alkyl- dered and completely dried in a vacuum desiccator phenols from ketone-phenol polymers was a over phosphorus pentoxide for several months, rather unexpected observation and the expression gave results upon quantitative analysis which “disproportionation” process was suggested by corresponded closely t o polymeric alkylenephevon Braun for this phenomenon. nols. The pyrolysis of the condensation products In all of the above investigations multimolar of phenols and the three cresols with the following quantities of phenol were used. It was the pur- aldehydes were studied. pose of the research set forth in this communicaFormaldehyde and phenol yielded a small tion t o investigate equimolar condensations of amount of a cresol. Acetaldehyde and phenol saturated aliphatic aldehydes with phenols to (I) and the three cresols (11, 111, IV) gave the establish experimentally the following: (a) whether corresponding ethylphenol and ethylcresols upon it is possible t o obtain mole for mole addition; pyrolysis of the Claisen solution soluble polymeric (b) whether these additions take place analogous condensation products. Substitution of vinyl to the addition of halogen acids or hydrocyanic acetate for acetaldehyde yielded similar polymers. acid t o the carbonyl bond, or whether the addition Propionaldehyde (V), n- and isobutyraldehyde (1) Presented before the Division of Organic Chemistry at the (VI, VII), n-valeric aldehyde (VIII) and n-heptalPittsburgh meeting of the American Chemical Society, September, dehyde (IX) and phenol gave the respective alkyl1938. (2) Several parts are taken from the thesis of S. Shapiro, presented phenols. These primary saturated alkylphenols to the Graduate School of New York University in partial fulfilment were purified by repeated fractional distillation, of the requirements for the degree of Master of Science. (3) Schmidlin and Lang, Ber., 43,2806 (1910); Claus and Trainer, then analyzed and further characterized as crys-
ibid., 1% 3009 (1888); Moehlau and Koch, ibid., 11, 283 (1878); L. Claisen, Ann., 237, 281 (1887); Th. Zincke, ibid.. 861, 256 (1908); E.K.Bolton, U. S. Patent 2,069.573 (1937); H. S. Rothrock, ibid., 2,069,580 (1937). (4) Dianin, J . Russ. 1’hys.-Chcm. Suc., 13, 540 (1891); Bcr., 26, 336 (1892); 1, V . B r d l l U , .Inn.,607, 15 ( 1 ‘ J S H ) .
(5) Niederl, Niederl and Reznek, THISJOURNAL, 68, 667 (1938); Weissberger, Be?., 44, 1438 (1911); Weger and Billmann, ibid., 36, 844 (1903); Kramer and Spilker, ibid., 29, 561 (1898); 33, 2280 (1900); 23, 3278 (1890), Moschner, ibid , 33, 737 (1900), Stoerncr and Boes, ibid., 33, 3018 (1900).
1114
J. B. NIEDERL,VICTORNIEDERL, S. SHAPIRO AND M. E. MCGREAL TABLE I
NO.
I
Phenol, HAC deriv.
#-EthylHAC deriv. I1 2-Methyl-4-ethylHAC I11 3-Methyl-4-ethylHAC 1x7 4-Methyl-2-ethylHAC V p-n-PropylHAC deriv. VI P-n-ButylHAC deriv. VI1 @-IsobutylHAC deriv. VI11 p-n-AmylHAC deriy. IX P-n-HeptylRAc deriv.
B. p , ‘C. Formulas 780 mm.
M.p., ‘C.
+D
s p . gr.a
C8Hio0 210-212 1.5239 1.0123 CloHlzOa 90 CgHlZO 223-228 1.5372 0.9944 CllHl4O8 125 .9956 CgH120 230-235 1.5362 CiiHi40s 131 CsHlsO 215-221 1 .5340 9949 CiiHiiOs 133 CgH120 228-230 1.5379 .999 CllH14Os 86 CioHirO 238-242 1.4981 .BiW ClzHlsOa 81 CioH140 235-239 1.5319 9796 ClgHIeOa 124-125 CiiHie.0 248-253 1,5272 .9621 clsHix08 90 ,9983 CisHaoO 271-278 15090 Cl&HzzOa 94
talline aryloxy-acetic acids, prepared according t o Shriner and FusoaB
Experimental p-Ethylphenol, p-Ethyl-o-cresol, p-Ethyl-m-cresol, oEthyl-+cresol.-Molar mixtures of phenol or cresol and acetaldehyde were placed in a 2-liter 3-necked roundbottomed flask provided with a reflux c o n d e w r , a thermometer and a gas inlet tube extending to the bottom of the vessel. Two hundred cc. of glacial acetic acid was added and the reaction mixture cooled to about -5’ by immersing the flask in an ice-salt mixture. A vigorous stream of dry hydrochloric acid gas was passed through the system for two hours and then the condensation product, a dark red oil, was poured into a large volume of cold water A yellowish white precipitate formed which was washed repeatedly with cold and hot water, then filtered and dried; yield, almost quantitative. The thoroughly dry product was powdered, placed in a 250-cc. distilling flask and distilled under atmospheric pressure. The distillate, consisting of water, the respective phenol or cresol and the alkylated ethylphenol or ethyl cresol was taken up in ethyl acetate, this solution dried mer calcium chloride and filtered. The solvent was distilled oA and the residue fractionally distilled under atmospheric pressure. The lower boiling portion (about 30%) consisted mostly of the original phenol or cresol; the higher boiling portion (about 40%) was redistilled and consisted of the respective ethylphenol or ethylcresol. A charred residue (about 20%) remained in the distilling flask after pyrolvsis. Axyloxyacetic Acid (HACDeriv.).-By the method of Shriner and Fuson, 1 g. of p-ethylphenol was dissolved in 5 cc. of a 33% sodium hydroxide solution and 1.5 g. of chloroacetic acid added. The mixture wa$ shaken thoroughly and heated o n a water-bath at 100 o for one hour. The solution was then diluted with 15 cc. of water, acidified with dilute hydrochloric acid to congo red and ex(6) Shriner and Fuson, “The Systematic Identification of Organic Compounds.” John Wiley and Sons, Inc., N e w York, 1935, p. 148.
’2%’ c
Calcd.
78.69 66.67 79.41 68.04 79.41 68 04 79.41 68.04 79.41 68.04
8.19 6.67 8.82 7.26 8 82 7 26 8 82 7 26 8 82 7 26 9.33 7 69 9 33 7 69 9 76 8 52 10 88 880
10 11 10 10
14 21 18 20 21
go.00 69.23 80.00 68.23 80 36 69.95 80.83 72.00
H
VOl. 59
Analyses,
%
N.E.
C
194 194 194 194
Found
H
N. E.
78.51 8.04 06.60 6 . 2 8 180 79.75 8 62 68.23 7.05 195 79 52 8 70 68.15 7 . 0 9 193 79 63 8.98 68.05 7.10 195 79.16 8.47 67.91 7.45 19ti 79.67 9.12 69 07 7.69 207 80.24 9.61 69.02 7.42 205 80.69 9.35 70.16 8 . 2 5 225 80.51 10.46 71.92 8.79 a51 ~
208 208 222 250
tracted with 50 cc. of ether. The ether was washed with an equal volume of water and then shaken out with 25 cc. of a 5% sodium carbonate solution. This solution was acidified with ditute hydrochloric acid and the p-ethylphenoxyacetic acid which precipitated out filtered and dried on porous tile. I t was recrystallized from diisobutylene. The cresoxyacetic acids were prepared in the same manner. plt-Propylphenol, p-n-Butylphenol, p-Isobutylphenol, pn-Amylphend, Fn-Heptylpheno1.-These compounds were prepared in a similar manner as described above, except that the reaction was carried out a t room temperature and condensation was complete in two and one-half to three hours. The temperature inside the reaction vessel rose to 60 to 80 ’ and diminishing temperature indicated completion of the reaction The condmsation product was then poured into cold water and a heavy oil separated out which was taken up in ethyl acetate. This solution was washed exhaustively with water, then dried and distilled under atmospheric pressure. The distillate, consisting of water, phenol and the corresponding alkylated phenol, was again taken u p in ethyl acetate, dried and fractionally distilled under reduced pressure. The higher boiling fraction, representing the respective alkylated phenol, was purified by redistillation. The yield ranged from 20 to 40%. The acetic acid derivatives were prepared as described above, except that wherever the final precipitate was an oil it was extracted from the aqueous solution with ether, the ether permitted to evaporate at room temperature, whereupon the acetic acid derivative crystallized. All the derivatives were recrystallized from diisobutylene.
The phenol coefficients given are the average of
six tests, performed in 30% alcoholic solution with staphylococcus azcreus a t 37’. The authors are indebted t o Dr. Wm. A. Feirer of the Mulfoxd Biological Laboratories, Glenolden, Pa., for performing these tests. The authors are further indebted to the Lambert Pharmacal Co., St. Louis,
June, 1937
DERIVATIVES OF U-HYDROXVPHENYLMERCLJRIC CHLORIDE
Mo., for a research grant €or the completion of this investigation.
Summary Equimolar condensations of monohydroxyphenols with saturated aliphatic aldehydes were studied. It was found that polymers result in quantitative yields. Upon slow pyrolysk, these
[CONTRI3UTION FROM
THE
lIf5
polymers yield the corresponding saturated primary alkylphenols. These types of condensations are being extended t o unsaturated and aromatic aldehydes, reLucing saccharides as well as to ketones, particularly cyclic ketones (cyclopentanone, cyclohexanone, alkyl cyclohexanones and camphor). RECEIVED MARCH4, 1937
NEWYORK,N. Y.
RESEARCH LABORATORIES O F THEUPJOHN COMPANY]
Some Derivatives of Ortho-Hydroxyphenylmercuric Chloride BY HANSP. ANDERSEN AND MERRILL C. HART In earlier reports it has been shown that variations in structure have a limited influence on bacteriostatic properties of organic mercury compounds, and that more complex structures were not as effective as mercury derivatives of hydrocarbons or phenols with limited substituents.2 One very effective mercurial was found to be ohydroxyphenylmercuric chloride, this compound also being bactericidal a t some dilutions.2 It seemed that possible derivatives of this compound could be prepared which would have similar properties. Some imide derivatives of phenylmercuric nitrate have been described as being used iii germicidal detergent or cosmetic cotnpositioiis.3 I n the present work some imide derivatives of ohydroxyphenylmercuric chloride have been prepared ai id their bacteriological properties evaluated.4 One has been found to be equally as good as the parent compound. I t w a s found that, in general, imide derivatives were readily formed in alkaline solution, especially if the imide contained a carbonyl group. An attempt was made to prepare derivatives of pyrrole, auramine, carbazole and piperidine but only in the case of piperidine was a product obtained in the form of the hydrochloride. This was formed in the absence of alkali. Although the simplest structures are most effective, it was thought that fatty acid derivatives might facilitate the in vivo activity by increasing diffusion inta the surfaces in contact with the (1) Hart and Andersen, THIS JOURNAL, 65, 2762 (1834). (2) Hart and Andersen, ibid., 6T, 1059 (1935). See also Photak and Leake, J . Pharmacol., 66, 265 (1936). (3) British Patent 432,689, July 31, 1935. (4) We are indebted to Mr. E A Gibson, Bacteriological Laboratory, for these results.
antiseptic. A few representative phenolmercuric fatty acid compounds have been prepared and described. The table gives the results obtained together with melting points and analytical data. TABLE r Compound with HOCsHiHgCl(o-) Succinimide Saccharine Phthalimide Piperidine Theobromine Barbituric acid Acetic acid Pelargonic dcirl Oleic acid Lauric acid Myristic acid Pdmitic arid Stearic acid
Yield,
% 72 3
53.7 96 3 79.3 51 48
...
60 7 ti4 a
74 72 !lo 70
hl. I,.,
'e.
232-235 242-243 223-224 126 145-165
...
150-151 13.5
!IS- 96 135.5-138.5 13S-l:lti' ix-i:ji 135-1378
1nhibitjng Mercury dilution t o analyses, % Slaph. a w e u s Calcd. Found in 5 min. 51.1 5 0 . 8 1--75,000"~" 42.5 43.1 1--10,000 45.5 4 5 . 6 I-PO.o(M 48.3' 47.8 1-30,OoU 10 3 1-10,000 66.1 56 3 1 -?O.(HHJ 56.8 a6.7 1 40.000 44.4 t34.8 40.6 38.5
m.5 34.7
44 1
I.?ll,lm
:
